Several publications are referenced in this application by numerals in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications is incorporated by reference herein.
Prostatic carcinoma is the most common malignant disease among men in the Western world, and benign prostatic hyperplasia is the most prevalent benign disease (1). In Western countries, it is estimated that men have approximately a 10% chance of developing prostate cancer and a 3-4% chance of dying of causes directly related to carcinoma of the prostate. The annual incidence of prostate cancer continues to increase, and this type of cancer now accounts for approximately 28% of all cancers in American men, compared to 18% in 1980 (1).
NE cells are a normal component of both the developing and mature prostatic epithelium. They produce a variety of neurosecretory products that exhibit growth-promoting activities, including parathyroid hormone-related peptides, neurotensin, serotonin, calcitonin and bombesin-related peptides, which suggests that these cells function through endocrine/paracrine mechanisms to regulate normal development and secretory activity of the prostate (2).
In a normal prostate, NE cells are distributed throughout the tissue and are readily detectable by microscopy as morphologically heterogeneous cells with irregular neurite-like processes extending between epithelial cells which often protrude into the lumen. NE cells may also be detected in prostate tissue by the presence of dense secretory vesicles (4-6). In prostate tumor tissue, NE cells often localize in clusters which increase in number with tumor progression (7).
Androgen ablation therapy (also known as hormonal deprivation therapy) is a well-established form of treatment for various stages of prostate cancer, especially advanced stages of cancer. However, this treatment alone does not cure the disease. During the course of androgen ablation therapy, prostate cancer cells will eventually lose their dependency on androgen and become highly aggressive. The molecular mechanism underlying this transition remains largely unknown. One hypothesis is that androgen ablation may result in the expansion of NE cells which in turn enhances the aggressiveness of the surrounding tumor cells because the NE cells secrete growth and motility promoting factors (3-5, 8-10).
Jiborn et al. (11) have shown that a marked increase in NE cell number is correlated with histopathologic tumor progression during androgen deprivation therapy, which suggests that resistance to hormonal therapy in prostate cancer may result from clonal proliferation of NE tumor cells. Interestingly, the proliferative index of neoplastic epithelial cells surrounding the NE cells is also often increased, which indicates that NE cells may act in a paracrine fashion by secreting growth-promoting factors, e.g., bombesin and neurotensin (12, 13).
Additionally, Bonkhoff et al. (14) have indicated that increases in the number of NE cells in prostate carcinomas occur either as a result of an increase in the stem cell population, which gives rise to NE cells in basal cells of normal prostate tissue, or by a process of trans-differentiation from malignant epithelial cells. The latter process may occur as tumor cells undergo de-differentiation steps (which are hallmarks of malignancy) and then, under certain circumstances, such as stimulation by differentiation inducing factors, a fraction of multipotent cells enter into a trans-differentiation program which results in the increase in NE cell population. The NE cells that undergo trans-differentiation may also be involved in hormone-refractory growth of prostate cancer. Alternatively, the population of NE cells may merely correlate with tumor volume (7).
Although there are a number of hypotheses describing the mechanism by which the NE cell population increases in the prostate, all of the possible mechanisms suggest that NE cells are associated with tumor growth.